This dissertation examines how public health officials, Native Hawaiians, and East Asian migrants transformed Honolulu from a placid mid–Pacific harbor into a vital disease–screening checkpoint for the Hawaiian Islands, the Pacific Basin, and America’s overseas empire. After 1850, steamship transportation further integrated Hawai‘i into a thriving Pacific World, rendering Honolulu a catalyst for the spread of infectious diseases. Microbial hitchhikers from abroad often appeared in Honolulu before resurfacing elsewhere in Hawai‘i or other Pacific seaports. While disproportionately plaguing the seaport’s Hawaiian and Chinese populations, these epidemic connections also threatened the security of transpacific mobility and America’s growing imperial influence. Alongside its role as a lucrative waystation, agricultural entrepôt, and budding naval rendezvous, I argue that Honolulu assumed a unique responsibility as America’s “sanitary sieve”—an urban clearinghouse that could filter out diseases traversing the Pacific. Public health officials engineered this municipal project by policing the sexuality, mobility, and physical bodies of Indigenous and immigrant communities; pitting vaccination programs against quarantine laws; and reconfiguring the city’s built and natural environments using innovative sanitary technologies. Such efforts did not go unchallenged however, as urbanites and islanders alike sought recourse through quotidian forms of resistance and Hawai‘i’s evolving court system. Ultimately, legal battles and public disputes over urban epidemics, racial difference, and medical authority in this mid–Pacific “paradise” tempered American imperial ascendancy beyond the western seaboard of the United States. The dissertation is divided into two sections, with each chapter dedicated to a case study of a single disease. Chapters 1 and 2 explore how legislators and municipal health officials targeted Honolulu’s indigenous population to halt the interisland diffusion of syphilis and smallpox. Chapters 3 and 4 investigate how turn-of-the-century health officials targeted Honolulu’s migrant enclaves, built environment, and urban wildlife to arrest the transpacific spread of cholera and bubonic plague. The conclusion considers the legacy of Hawaiian public health programs by focusing on the completion of the Panama Canal—an event that ruptured a seemingly self-contained Pacific World, amplified the scale of global trade, and directly tethered Honolulu to mid-Atlantic seaports where mosquito-borne diseases like yellow fever were endemic.